Recombinant DNA technology has been widely used to produce new protein drugs for biomedical applications. Two problems of concern to the biopharmaceutical industry are 1) how to increase protein refolding yields during protein production processes and 2) how to maintain athe stability of folded, biologically-active proteins during packing, shipping, and storage after production. In order to address these problems, one needs a comprehensive understanding of the detailed mechanisms by which aqueous environments influence protein stability and protein folding. The aim of this proposal is to develop a simple but realistic model that explains solute-mediated protein denaturation and stabilization on a molecular level. The ultimate goal of the proposed research is to develop a statistical mechanical theory that predicts how and when proteins fold, unfold and aggregate as a function of temperature, pH, and the concentration of solutes (salt, denaturant, or cosolvent). The proposed off-lattice protein model is to designed that 1) equilibrium stimulations of protein folding are possible and 2) statistical mechanical theoretical tools are available. Three approaches (an analytical theory, a numerical theory, and computer simulations) that have increasing levels of sophistication are suggested.